Abstract
Cardiotoxins (CTXs) are suggested to exert their cytotoxicity through cell membrane damage. Other studies show that penetration of CTXs into cells elicits mitochondrial fragmentation or lysosome disruption, leading to cell death. Considering the role of AMPK-activated protein kinase (AMPK) in mitochondrial biogenesis and lysosomal biogenesis, we aimed to investigate whether the AMPK-mediated pathway modulated Naja atra (Taiwan cobra) CTX3 cytotoxicity in U937 human leukemia cells. Our results showed that CTX3 induced autophagy and apoptosis in U937 cells, whereas autophagic inhibitors suppressed CTX3-induced apoptosis. CTX3 treatment elicited Ca2+-dependent degradation of the protein phosphatase 2A (PP2A) catalytic subunit (PP2Acα) and phosphorylation of AMPKα. Overexpression of PP2Acα mitigated the CTX3-induced AMPKα phosphorylation. CTX3-induced autophagy was via AMPK-mediated suppression of the Akt/mTOR pathway. Removal of Ca2+ or suppression of AMPKα phosphorylation inhibited the CTX3-induced cell death. CTX3 was unable to induce autophagy and apoptosis in U937 cells expressing constitutively active Akt. Met-modified CTX3 retained its membrane-perturbing activity, however, it did not induce AMPK activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca2+/PP2A/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction.
Highlights
Cobra cardiotoxins (CTXs) show a wide range of biological activities including hemolysis, cardiotoxicity, and disruption of muscular integrity [1,2,3]
Activation and death of U937 cells. These results conclusively indicate that CTX3 induces autophagy and apoptosis in U937 cells via the Ca2+ /phosphatase 2A (PP2A)/AMPK axis, and suggest that the membrane-perturbing activity of CTX3 is not crucial for the cell death signaling pathway induction
Death induced by CTX3 (Figure 1D). These results indicated that CTX3 induces apoptosis in U937 cells
Summary
Cobra cardiotoxins (CTXs) show a wide range of biological activities including hemolysis, cardiotoxicity, and disruption of muscular integrity [1,2,3]. Accumulated evidence has shown that CTXs induce apoptosis in cancer cells through the mitochondria-mediated apoptotic pathway, lysosome-mediated death pathway, or membrane-damaging effects [4,5,6,7,8]. Some studies indicate that the cytotoxicity of CTXs is related to their capability of cell penetration [4,7,10,11]. The internalized CTXs are suggested to elicit mitochondrial fragmentation [10,11] or lysosome disruption [4,7], and thereby induce the death of the myoblast cells, primary cortical neurons, or cancer cells.
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